Insights into 4-hydroxyphenylpyruvate dioxygenase-inhibitor interactions from comparative structural biology

4-Hydroxyphenylpyruvate dioxygenase (HPPD) plays a key role in tyrosine me-tabolism and has been identified as a promising target for herbicide and drug discovery. The structures of HPPD complexed with different types of inhibitors have been determined previously. We summarize the structures of HPPD com-plexed with structurally diverse molecules, including inhibitors, natural products, substrates, and catalytic intermediates; from these structures, the detailed inhib-itory mechanisms of different inhibitors were analyzed and compared, and the key structural factors determining the slow-binding behavior of inhibitors were identified. Further, we propose four subpockets that accommodate different in-hibitor substructures. We believe that these analyses will facilitate in-depth un-derstanding of the enzymatic reaction mechanism and enable the design of new inhibitors with higher potency and selectivity.

Automated summary

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial enzyme in tyrosine metabolism and a potential target for herbicide and drug discovery. This study summarizes the structures of HPPD complexed with various molecules and analyzes the inhibitory mechanisms of different inhibitors. By identifying key structural factors, the study provides insights into the design of new inhibitors with enhanced potency and selectivity.